Lung endothelium has historically been considered a homogeneous and metabolically inactive cell layer. However, we now know that lung endothelium is richly diverse in structure and function, and actively participates in normal vascular homeostasis, the response to lung injury, and vascular repair following injury. This Program Project Grant is founded on the hypothesis that endothelium lining the lung's extra-alveolar and alveolar blood vessels is phenotypically distinct, and that the unique behaviors of cells from these different vascular locations is necessary for them to fulfill their site-specific functions. Indeed, work from multiple investigators in our program project grant has resolved a demarcation at approximately 25 pm in vascular diameter, where extra-alveolar vessels transition into the capillary plexus to become alveolar vessels, that is associated with a prominent change in endothelial cell phenotype. The pulmonary microvascular endothelial cells that reside within the alveolar vessels possess a tighter barrier function than do their macrovascular counterparts, have higher metabolic activity, and migrate and proliferate at a high rate, due at least in part to the enriched number of progenitor cells that reside within this vascular niche. In total, we know very little about the cells that make-up the alveolar capillary bed. Therefore, in this funding cycle (2006-2011), four inter-related projects have been supported, which collectively seek to address fundamentally important signal transduction networks that are responsible for pulmonary microvascular endothelial cell barrier function, susceptibility to apoptosis/necrosis, and regulation of hemostasis and coagulation. Project 3 was initially supported for three years, to examine whether calcium entry through T-type calcium channels is an important amplification step in release of von Willebrand factor and upregulation of P-selectin, specifically within capillary endothelial cells. Great strides have been made toward completing the specific aims in project 3, and critical new directions that greatly complement the program project grant have been developed. Thus, this competitive supplement seeks two years of additional support for project 3, extending through this application's funding cycle in 2011.